scholarly journals Differential Innate Immune Responses Elicited by Nipah Virus and Cedar Virus Correlate with Disparate In Vivo Pathogenesis in Hamsters

Viruses ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 291 ◽  
Author(s):  
Tony Schountz ◽  
Corey Campbell ◽  
Kaitlyn Wagner ◽  
Joel Rovnak ◽  
Cynthia Martellaro ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Syrian Hamster ◽  
Nipah Virus ◽  
Neutralizing Antibody ◽  
Type I ◽  
Type I Ifn ◽  
Innate Immune Responses ◽  
Syrian Hamsters ◽  
Pulmonary Endothelial Cells

Syrian hamsters (Mesocricetus auratus) are a pathogenesis model for the Nipah virus (NiV), and we sought to determine if they are also susceptible to the Cedar virus (CedPV). Following intranasal inoculation with CedPV, virus replication occurred in the lungs and spleens of infected hamsters, a neutralizing antibody was produced in some hamsters within 8 days post-challenge, and no conspicuous signs of disease occurred. CedPV replicated to a similar magnitude as NiV-Bangladesh in type I IFN-deficient BHK-21 Syrian hamster fibroblasts but replicated 4 logs lower in type I IFN-competent primary Syrian hamster and human pulmonary endothelial cells, a principal target of henipaviruses. The coinfection of these cells with CedPV and NiV failed to rescue CedPV titers and did not diminish NiV titers, suggesting the replication machinery is virus-specific. Type I IFN response transcripts Ifna7, Ddx58, Stat1, Stat2, Ccl5, Cxcl10, Isg20, Irf7, and Iigp1 were all significantly elevated in CedPV-infected hamster endothelial cells, whereas Ifna7 and Iigp1 expression were significantly repressed during NiV infection. These results are consistent with the hypothesis that CedPV’s inability to counter the host type I IFN response may, in part, contribute to its lack of pathogenicity. Because NiV causes a fatal disease in Syrian hamsters with similarities to human disease, this model will provide valuable information about the pathogenic mechanisms of henipaviruses.

552 SUMOylation inhibitor TAK-981 activates NK cells and macrophages via Type I interferon signaling and shows synergistic activity in combination with rituximab and daratumumab in preclinical models

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A588-A588
Author(s):  
Akito Nakamura ◽  
Keli Song ◽  
Stephen Grossman ◽  
Kristina Xega ◽  
Yuhong Zhang ◽  
...  
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Phase 1 ◽  
Neutralizing Antibody ◽  
Type I ◽  
Synergistic Activity ◽  
Type I Ifn ◽  
Innate Immune Responses ◽  
Preclinical Models ◽  
Xenograft Models

BackgroundTAK-981 is a first-in-class small molecule inhibitor of the SUMO activating enzyme in Phase 1 clinical trials. SUMOylation has previously been implicated in the regulation of innate immune responses and expression of Type I interferons,1 and ex vivo treatment of human and mouse immune cells with TAK-981 results in transcriptional upregulation of IFN-beta and Type I IFN receptor (IFNAR) signaling. We previously showed that TAK-981 increases NK cell activation and M1 macrophage polarization, leading to enhanced ADCC and ADCP in the presence of rituximab.2In vivo, TAK-981 induces IFNAR-dependent antitumor activity and synergizes with rituximab in xenograft-bearing mice.2 3 Here we investigated the mechanism of synergistic activity with rituximab and evaluated the combination of TAK-981 with daratumumab, another therapeutic mAb.MethodsThe role of effector function of rituximab in the mechanism of synergy with TAK-981 was evaluated in OCI-Ly10-bearing SCID mice treated with TAK-981 and the LALA-PG version of rituximab, in which mutations in the Fc region prevent FcγR binding. The combination of TAK-981 and rituximab was also evaluated in OCI-Ly10 tumor-bearing mice in which macrophages and/or NK cells were depleted with clodronate and anti-asialo GM1. TAK-981 in combination with daratumumab was evaluated in two CD38+ xenograft models, Daudi (Burkitt’s lymphoma) and LP-1 (multiple myeloma). To test ADCP activity, Daudi-KILR cells were incubated with human monocyte-derived macrophages (hMDM) treated with TAK-981 in the presence or absence of rituximab or daratumumab, with or without a neutralizing antibody to IFNAR2.ResultsUnlike rituximab, LALA-PG mutated rituximab did not synergize with TAK-981 in OCI-Ly10 tumor-bearing mice, indicating a requirement for Fc effector function. Depletion of macrophages with clodronate or NK cells with anti-asialo GM1 lessened the anti-tumor effect of the TAK-981 and rituximab combination, while dual depletion of macrophages and NK cells had a greater impact. TAK-981 showed synergistic activity in combination with daratumumab in two CD38+ xenograft models, Daudi and LP-1. In vitro, TAK-981-treated hMDM showed increased phagocytic activity against Daudi cells, and this effect was further enhanced in the presence of rituximab or daratumumab but prevented by a neutralizing antibody to IFNAR2.ConclusionsIn preclinical models, TAK-981 synergizes with rituximab through a mechanism involving Type I-IFN dependent enhancement of ADCC and ADCP, and the combination of TAK-981 with daratumumab is also synergistic.ReferencesDecque A, Joffre O, Magalhaes JG, Cossec J-C, Blecher-Gonen R, Lapaquette P, Silvin A, Manel N, Joubert P-E, Seeler J-S, Albert ML, Amit I, Amigorena S, Dejean A. Sumoylation coordinates the repression of inflammatory and anti-viral gene-expression programs during innate sensing. Nat Immunol 2016;17:140–149.Nakamura A, Grossman S, Song K, Idamakanti N, Shaprio G, Huszar D. Inhibition of SUMOylation by TAK-981 induces antitumor innate immune responses by modulating macrophage and NK cell function through Type I IFN pathway activation [abstract]. In: Proceedings of the American Association forCancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Cancer Res 2019;79(13 Suppl):Abstract nr 1523.Huszar D. TAK-981: A first-in-class SUMOylation inhibitor in phase 1 clinical trials promotes a Type I interferon response and antitumor immunity in preclinical models. AACR Annual Meeting 2019, American Association for Cancer Research; Mar 29-Apr 03; Atlanta, GA, US. Session DDT01.

scholarly journals pMGF505-7R determines pathogenicity of African swine fever virus infection by inhibiting IL-1β and type I IFN production

2021 ◽  
Vol 17 (7) ◽  
pp. e1009733
Author(s):  
Jiangnan Li ◽  
Jie Song ◽  
Li Kang ◽  
Li Huang ◽  
Shijun Zhou ◽  
...  
Keyword(s):  
Immune Responses ◽  
Inflammatory Responses ◽  
African Swine Fever Virus ◽  
African Swine Fever ◽  
Innate Immune ◽  
Fever Virus ◽  
Type I ◽  
Type I Ifn ◽  
Innate Immune Responses

Inflammatory factors and type I interferons (IFNs) are key components of host antiviral innate immune responses, which can be released from the pathogen-infected macrophages. African swine fever virus (ASFV) has developed various strategies to evade host antiviral innate immune responses, including alteration of inflammatory responses and IFNs production. However, the molecular mechanism underlying inhibition of inflammatory responses and IFNs production by ASFV-encoded proteins has not been fully understood. Here we report that ASFV infection only induced low levels of IL-1β and type I IFNs in porcine alveolar macrophages (PAMs), even in the presence of strong inducers such as LPS and poly(dA:dT). Through further exploration, we found that several members of the multigene family 360 (MGF360) and MGF505 strongly inhibited IL-1β maturation and IFN-β promoter activation. Among them, pMGF505-7R had the strongest inhibitory effect. To verify the function of pMGF505-7R in vivo, a recombinant ASFV with deletion of the MGF505-7R gene (ASFV-Δ7R) was constructed and assessed. As we expected, ASFV-Δ7R infection induced higher levels of IL-1β and IFN-β compared with its parental ASFV HLJ/18 strain. ASFV infection-induced IL-1β production was then found to be dependent on TLRs/NF-κB signaling pathway and NLRP3 inflammasome. Furthermore, we demonstrated that pMGF505-7R interacted with IKKα in the IKK complex to inhibit NF-κB activation and bound to NLRP3 to inhibit inflammasome formation, leading to decreased IL-1β production. Moreover, we found that pMGF505-7R interacted with and inhibited the nuclear translocation of IRF3 to block type I IFN production. Importantly, the virulence of ASFV-Δ7R is reduced in piglets compared with its parental ASFV HLJ/18 strain, which may due to induction of higher IL-1β and type I IFN production in vivo. Our findings provide a new clue to understand the functions of ASFV-encoded pMGF505-7R and its role in viral infection-induced pathogenesis, which might help design antiviral agents or live attenuated vaccines to control ASF.

scholarly journals Photosensitivity and type I IFN responses in cutaneous lupus are driven by epidermal-derived interferon kappa

2018 ◽  
Vol 77 (11) ◽  
pp. 1653-1664 ◽  
Author(s):  
Mrinal K Sarkar ◽  
Grace A Hile ◽  
Lam C Tsoi ◽  
Xianying Xing ◽  
Jianhua Liu ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Lupus Erythematosus ◽  
Cutaneous Lupus Erythematosus ◽  
Ultraviolet B ◽  
Immunofluorescent Staining ◽  
Tunel Staining ◽  
Type I ◽  
Type I Ifn ◽  
Cutaneous Lupus

ObjectiveSkin inflammation and photosensitivity are common in patients with cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE), yet little is known about the mechanisms that regulate these traits. Here we investigate the role of interferon kappa (IFN-κ) in regulation of type I interferon (IFN) and photosensitive responses and examine its dysregulation in lupus skin.MethodsmRNA expression of type I IFN genes was analysed from microarray data of CLE lesions and healthy control skin. Similar expression in cultured primary keratinocytes, fibroblasts and endothelial cells was analysed via RNA-seq. IFNK knock-out (KO) keratinocytes were generated using CRISPR/Cas9. Keratinocytes stably overexpressing IFN-κ were created via G418 selection of transfected cells. IFN responses were assessed via phosphorylation of STAT1 and STAT2 and qRT-PCR for IFN-regulated genes. Ultraviolet B-mediated apoptosis was analysed via TUNEL staining. In vivo protein expression was assessed via immunofluorescent staining of normal and CLE lesional skin.ResultsIFNK is one of two type I IFNs significantly increased (1.5-fold change, false discovery rate (FDR) q<0.001) in lesional CLE skin. Gene ontology (GO) analysis showed that type I IFN responses were enriched (FDR=6.8×10−04) in keratinocytes not in fibroblast and endothelial cells, and this epithelial-derived IFN-κ is responsible for maintaining baseline type I IFN responses in healthy skin. Increased levels of IFN-κ, such as seen in SLE, amplify and accelerate responsiveness of epithelia to IFN-α and increase keratinocyte sensitivity to UV irradiation. Notably, KO of IFN-κ or inhibition of IFN signalling with baricitinib abrogates UVB-induced apoptosis.ConclusionCollectively, our data identify IFN-κ as a critical IFN in CLE pathology via promotion of enhanced IFN responses and photosensitivity. IFN-κ is a potential novel target for UVB prophylaxis and CLE-directed therapy.

scholarly journals Mechanical control of innate immune responses against viral infection revealed in a human Lung Alveolus Chip

2021 ◽  
Author(s):  
Haiqing Bai ◽  
Longlong Si ◽  
Amanda Jiang ◽  
Chaitra Belgur ◽  
Roberto Plebani ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Immune Responses ◽  
Viral Infection ◽  
Human Lung ◽  
Innate Immune ◽  
H3n2 Virus ◽  
Type I ◽  
Innate Immune Responses ◽  
Lung Alveolus

ABSTRACTMechanical forces associated with breathing play a fundamental role in lung development and disease but the molecular pathways remain largely unknown. Here, we used a mechanically actuatable Human Lung Alveolus Chip that recapitulates human lung alveolar type I and type II cell differentiation, alveolar-capillary interface formation, and genome-wide gene expression profiles characteristic of the distal lung to investigate the role of physical forces associated with cyclic breathing motions in lung innate immune responses to viral infection. When the mechanically active Alveolus Chips are infected with the influenza H3N2 virus, a cascade of host responses is elicited on-chip, including increased production of cytokines and expression of inflammation-associated genes in pulmonary epithelial and endothelial cells, resulting in enhanced recruitment of circulating immune cells as occurs during viral infection in vivo. Surprisingly, studies carried out in parallel with static chips revealed that physiological breathing motions suppress viral replication by activating protective innate immune responses in epithelial and endothelial cells. This is mediated at least in part through upregulation of S100 calcium-binding protein A7 (S100A7), which binds to the Receptor for Advanced Glycation End Products (RAGE), an inflammatory mediator that is most highly expressed in the lung alveolus in vivo. This mechano-immunological control mechanism is further supported by the finding that existing RAGE inhibitor drugs can suppress the production of inflammatory cytokines in response to influenza virus infection in this model. S100A7-RAGE interactions and modulation of mechanical ventilation parameters could therefore serve as new targets for therapeutic intervention in patients infected with influenza and other potential pandemic viruses that cause life-threatening lung inflammation.

scholarly journals Type I Interferon Released by Myeloid Dendritic Cells Reversibly Impairs Cytomegalovirus Replication by Inhibiting Immediate Early Gene Expression

2015 ◽  
Vol 89 (19) ◽  
pp. 9886-9895 ◽  
Author(s):  
Julia Katharina Holzki ◽  
Franziska Dağ ◽  
Iryna Dekhtiarenko ◽  
Ulfert Rand ◽  
Rosaely Casalegno-Garduño ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Dendritic Cells ◽  
Viral Latency ◽  
Immediate Early ◽  
Type I ◽  
Type I Ifn ◽  
Myeloid Dendritic Cells

ABSTRACTCytomegalovirus (CMV) is a ubiquitous beta-herpesvirus whose reactivation from latency is a major cause of morbidity and mortality in immunocompromised hosts. Mouse CMV (MCMV) is a well-established model virus to study virus-host interactions. We showed in this study that the CD8-independent antiviral function of myeloid dendritic cells (mDC) is biologically relevant for the inhibition of MCMV replicationin vivoandin vitro. In vivoablation of CD11c+DC resulted in higher viral titers and increased susceptibility to MCMV infection in the first 3 days postinfection. We developedin vitrococulture systems in which we cocultivated MCMV-infected endothelial cells or fibroblasts with T cell subsets and/or dendritic cells. While CD8 T cells failed to control MCMV replication, bone marrow-derived mDC reduced viral titers by a factor of up to 10,000. Contact of mDC with the infected endothelial cells was crucial for their antiviral activity. Soluble factors secreted by the mDC blocked MCMV replication at the level of immediate early (IE) gene expression, yet the viral lytic cycle reinitiated once the mDC were removed from the cells. On the other hand, the mDC did not impair MCMV replication in cells deficient for the interferon (IFN) alpha/beta receptor (IFNAR), arguing that type I interferons were critical for viral control by mDC. In light of our recent observation that type I IFN is sufficient for the induction of latency immediately upon infection, our results imply that IFN secreted by mDC may play an important role in the establishment of CMV latency.IMPORTANCENumerous studies have focused on the infection of DC with cytomegaloviruses and on the establishment of latency within them. However, almost all of these studies have relied on the infection of DC monoculturesin vitro, whereas DC are just one among many cell types present in an infection sitein vivo. To mimic this aspect of thein vivosituation, we cocultured DC with infected endothelial cells or fibroblasts. Our data suggest that direct contact with virus-infected endothelial cells activates CD11c+DC, which leads to reversible suppression of MCMV replication at the level of IE gene expression by a mechanism that depends on type I IFN. The effect matches the formal definition of viral latency. Therefore, our data argue that the interplay of dendritic cells and infected neighboring cells might play an important role in the establishment of viral latency.

scholarly journals Essential role of IPS-1 in innate immune responses against RNA viruses

2006 ◽  
Vol 203 (7) ◽  
pp. 1795-1803 ◽  
Author(s):  
Himanshu Kumar ◽  
Taro Kawai ◽  
Hiroki Kato ◽  
Shintaro Sato ◽  
Ken Takahashi ◽  
...  
Keyword(s):  
Rna Viruses ◽  
Rna Virus ◽  
Critical Role ◽  
Nuclear Factor Κb ◽  
Type I ◽  
Innate Immune Responses ◽  
Antiviral Responses ◽  
Deficient Mice

IFN-β promoter stimulator (IPS)-1 was recently identified as an adapter for retinoic acid–inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (Mda5), which recognize distinct RNA viruses. Here we show the critical role of IPS-1 in antiviral responses in vivo. IPS-1–deficient mice showed severe defects in both RIG-I– and Mda5-mediated induction of type I interferon and inflammatory cytokines and were susceptible to RNA virus infection. RNA virus–induced interferon regulatory factor-3 and nuclear factor κB activation was also impaired in IPS-1–deficient cells. IPS-1, however, was not essential for the responses to either DNA virus or double-stranded B-DNA. Thus, IPS-1 is the sole adapter in both RIG-I and Mda5 signaling that mediates effective responses against a variety of RNA viruses.

Expression of CD34 in Pulmonary Endothelial Cells in vivo1

Pathobiology ◽  
2002 ◽  
Vol 70 (1) ◽  
pp. 11-17 ◽  
Author(s):  
Annette M. Müller ◽  
Maya Nesslinger ◽  
Guido Skipka ◽  
Klaus-Michael Müller
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Endothelial Cells

scholarly journals The Matrix Protein of Nipah Virus Targets the E3-Ubiquitin Ligase TRIM6 to Inhibit the IKKε Kinase-Mediated Type-I IFN Antiviral Response

2016 ◽  
Vol 12 (9) ◽  
pp. e1005880 ◽  
Author(s):  
Preeti Bharaj ◽  
Yao E. Wang ◽  
Brian E. Dawes ◽  
Tatyana E. Yun ◽  
Arnold Park ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Matrix Protein ◽  
Nipah Virus ◽  
E3 Ubiquitin Ligase ◽  
Antiviral Response ◽  
Type I ◽  
Type I Ifn ◽  
The Matrix

scholarly journals Innate triggering and antiviral effector functions of activin A

2021 ◽  
Author(s):  
Kinda Al-Hourani ◽  
Narayan Ramamurthy ◽  
Emanuele Marchi ◽  
Ruth M Eichinger ◽  
Lian N Lee ◽  
...  
Keyword(s):  
Viral Infection ◽  
Influenza A ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Activin A ◽  
Type I ◽  
Type I Ifn ◽  
Effector Functions

First-line defence against viral infection is contingent upon rapid detection of conserved viral structural and genomic motifs by germline-encoded pattern recognition receptors, followed by activation of the type I IFN system and establishment of an intracellular antiviral state. Novel antiviral functions of bone morphogenetic protein and related activin cytokines, acting in conjunction with, and independently of, type I IFN, have recently been described. Activin A mediates multiple innate and adaptive immune functions, including antiviral effects. However, how such effects are mediated and how activin might be triggered by viral infection have not been defined. Here we addressed this in vivo and in vitro, in humans and mice. Transcriptomic analyses delineated strikingly congruent patterns of gene regulation in hepatocytes stimulated with recombinant activin A and IFNα in vitro. Activin A mRNA, encoded by INHBA, is induced upon activation of RIG-I, MDA5 and TLR7/8 viral nucleic acid sensors in vitro, across multiple cell lines and in human peripheral blood mononuclear cells. In vivo, infection of mice with influenza A also upregulated Inhba mRNA in the lung; this local upregulation of Inhba is retained in MAVS knockout mice, indicating a role for non-RIG-I-like receptors in its induction. Activin induction and signalling were also detectable in patients with chronic viral hepatitis. Together, these data suggest Activin A is triggered in parallel with type I IFN responses and can trigger related antiviral effector functions. This model has implications for the development of targeted antiviral therapies, in addition to revealing novel facets of activin biology.

scholarly journals cGAS-STING Signaling Regulates Initial Innate Control of Cytomegalovirus Infection

2016 ◽  
Vol 90 (17) ◽  
pp. 7789-7797 ◽  
Author(s):  
Chan-Wang J. Lio ◽  
Bryan McDonald ◽  
Mariko Takahashi ◽  
Rekha Dhanwani ◽  
Nikita Sharma ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Viral Replication ◽  
Acute Infection ◽  
Type I ◽  
Human Endothelial Cells ◽  
Cmv Infection ◽  
Inflammatory Conditions ◽  
Sting Pathway ◽  
Human Cmv

ABSTRACTSeveral innate sensing pathways contribute to the control of early cytomegalovirus (CMV) infection, leading to a multiphasic type I interferon (IFN-I) response that limits viral replication and promotes host defenses. Toll-like receptor (TLR)-dependent pathways induce IFN-I production in CMV-infected plasmacytoid dendritic cells; however, the initial burst of IFN-I that occurs within the first few hoursin vivois TLR independent and emanates from stromal cells. Here we show that primary human endothelial cells mount robust IFN-I responses to human CMV that are dependent upon cyclic GMP-AMP synthase (cGAS), STING, and interferon regulatory factor 3 (IRF3) signaling. Disruption of STING expression in endothelial cells by clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 revealed that it is essential for the induction of IFN-I and restriction of CMV replication. Consistently, STING was necessary to mount the first phase of IFN-I production and curb CMV replication in infected mice. Thus, DNA sensing through STING is critical for primary detection of both human and mouse CMV in nonhematopoietic cells and drives the initial wave of IFN-I that is key for controlling early viral replicationin vivo.IMPORTANCECytomegalovirus (CMV) is one of the most common viral pathogens, with the majority of people contracting the virus in their lifetime. Although acute infection is mostly asymptomatic in healthy persons, significant pathology is observed in immunocompromised individuals, and chronic CMV infection may exacerbate a myriad of inflammatory conditions. Here we show that primary human endothelial cells mount robust IFN-I responses against CMV via a cGAS/STING/IRF3 pathway. Disruption of STING expression by CRISPRs revealed an essential role in eliciting IFN-I responses and restricting CMV replication. Consistently, in mice, STING is necessary for the first phase of IFN-I production that limits early CMV replication. Our results demonstrate a pivotal role for the cGAS-STING pathway in the initial detection of CMV infection.

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